Retinitis Pigmentosa (RP) är en ögonsjukdom som leder till blindhet, sjukdomsförloppet varierar från individ till individ och det finns för närvarande ingen botande behandling. Att utveckla en synskada successivt och bli tvungen att anpassa sig efter en ny vardag skapar osäkerhet och ett stort lidande. Hjälpmedel som underlättar vardagen mottages motvilligt och den synskadade förnekar vanligtvis sin situation. Som sjuksköterska är det viktigt att ha förståelse för den synskadades situation och lidande för att kunna skapa en god vårdrelation. Problemet är att det finns lite forskning inom området, vilket leder till upprepade missförstånd och ett vårdlidande för patienten. Syftet med studien är att beskriva hur det är att leva med vetskapen om att ha en sjukdom som leder till blindhet och hur den förändrande vardagen upplevs och hanteras. Vi har valt att analysera biografier för att få patientens beskrivning av sin subjektiva upplevelse och den metod som Dahlborg Lyckhage beskriver har stått till grund för analysen. I analysen framkom fyra huvudteman med underteman som ligger till grund för resultatet. De fyra huvudtemana är: svårigheter med att acceptera sin sjukdom, de första stegen till hantering, att bli sedd som blind och att bli vän med sin sjukdom. Vi har funnit liknande resultat i andras studier och resultatet upplevs som relevant för den vård som sjuksköterskan praktiserar. Det är viktigt att synliggöra och uppmärksamma dessa personers livsvärld då RP är en vanlig ögonsjukdom och det är omöjligt att veta när en synskadad patient kommer in genom dörren till avdelningen. / <p>Program: Sjuksköterskeutbildning</p><p>Uppsatsnivå: C</p>

Inherited retinal degenerations are a group of disorders characterised by great genetic heterogeneity. Clinically, they can be divided into two large groups of diseases, those associated with night blindness, e.g. retinitis pigmentosa (RP), and those with macular malfunction, e.g. cone/cone-rod dystrophy (COD/CORD). This thesis is focused on finding the genetic basis of disease in families with autosomal dominant COD, autosomal dominant RP, and Bothnia dystrophy (BD), a regional variant of RP.   A variant of COD was previously mapped to 17p12-p13 in a family from northern Sweden. One additional family originating from the same geographical area was included in fine mapping of this chromosome region. Using 12 microsatellite markers in linkage and haplotype analysis, the region was refined from 26.9 to 14.3 cM. A missense mutation, Q626H, in an evolutionarily conserved region of PITPNM3, phosphatidylinositol transfer membrane-associated protein, was identified. The mutation segregated with the disease in both families and was absent from normal control chromosomes. PITPNM3 is a human homologue of the Drosophila retinal degeneration (rdgB) protein, which is highly expressed in the retina and has been proposed to be required for membrane turnover of photoreceptor cells. With the intention of establishing the global impact that PITPNM3 has on retinal degenerations 165 DNA samples from COD and CORD patients were obtained from Denmark, Germany, the UK, and USA and screened for mutations. The Q626H mutation found in the Swedish families was also found in one British family and a novel Q342P variant was detected in a German patient. In addition, two intronic variants were identified: c.900+60C&gt;T and c.901-45G&gt;A. Thus, we concluded that mutations in PITPNM3 represent a rare cause of COD worldwide. In two large families from northern Sweden showing autosomal dominant RP with reduced penetrance, the disease locus was mapped using genome-wide linkage analysis to 19q13.42 (RP11). Since mutation screening of eight genes on 19q13.42 revealed no mutations, multiplex ligation-dependent probe amplification (MLPA) was used to screen for large genomic abnormalities in PRPF31, RHO, RP1, RPE65, and IMPDH1. A large deletion spanning 11 exons of PRPF31 and three genes upstream was identified. Using long-range PCR, the breakpoints of the deletion were identified and the size of the deletion was determined to encompass almost 59 kb. BD is an autosomal recessive type of RP with high prevalence in northern Sweden. The disease is associated with a c.700C&gt;T mutation in RLBP1. In a screening of recessive RP in northern Sweden, 67 patients were found to be homozygous for c.700C&gt;T and 10 patients were heterozygous. An evaluation with arrayed primer extension (APEX) technology revealed a second mutation, c.677T&gt;A, in RLBP1 giving rise to compound heterozygosity in these patients. In addition, a c.40C&gt;T exchange in CAIV was detected in a patient with BD and in 143 healthy blood donors. The c.40C&gt;T substitution in CAIV has been reported to cause autosomal dominant RP in South African families with European ancestry. However, in the population of northern Sweden it appears to be a benign polymorphism. In summary, a first mutation in PITPNM3, encoding a human homologue of the Drosophila retinal degeneration protein, was detected in two large families with COD. A large deletion in PRPF31 was discovered in two families with autosomal dominant RP showing reduced penetrance and in 10 patients BD was shown to be caused by two allelic mutations in RLBP1.

Human cytomegalovirus (HCMV) is a betaherpesvirus that infects up to 80% of the population worldwide, and establishes latency in monocytes and bone marrow cells. Reactivated HCMV can become an opportunistic pathogen in individuals who are immunocompromised, such as those with acquired immunodeficiency syndrome (AIDS). HCMV infection of AIDS patients causes a sight-threatening retinitis that leads to vision loss and blindness in up to 46% of this population without antiretroviral treatment. Because untreated HIV-infected individuals exhibit the loss of cell-mediated immunity and alterations in CD4+ T-helper (Th) cell cytokines, including elevation of interleukin-4 (IL-4), IL-10, and IL-17, we sought to test the hypothesis that these cytokines play key roles in governing the susceptibility to AIDS-related HCMV retinitis. This hypothesis was tested utilizing a clinically relevant mouse model of experimental murine cytomegalovirus (MCMV) retinitis that occurs in C57BL/6 mice immunosuppressed by mouse retroviruses (MAIDS). Studies revealed that MAIDS progression was associated with increased levels of IL-4 and IL-10, cytokines whose production has been associated with diminished CD8+ T-cell-mediated immunity during HIV infection. However, MCMV–infected eyes of retinitis-susceptible IL-4-/- or IL-10-/- MAIDS mice exhibited frequency and severity of retinitis and viral titers equivalent to MCMV-infected eyes of wild-type MAIDS animals. These studies indicated that neither IL-4 nor IL-10 alone play key roles in increased susceptibility to MCMV retinitis. In comparison, IL-17, an inflammatory cytokine associated with the ocular autoimmune disease uveitis, was systemically increased during the progression of MAIDS, but MCMV-infected eyes of retinitis-susceptible MAIDS mice exhibited a significant reduction in IL-17. These findings suggested that IL-17 plays no direct role in the pathogenesis of experimental MCMV retinitis. However, these results also suggested the remarkable possibility that MCMV downregulates IL-17 production, a hypothesis supported by the observation that systemic MCMV infection of healthy and MAIDS mice resulted in the downregulation of IL-17. Mechanistic studies revealed that knockdown of IL-10 resulted in a partial recovery IL-17 levels during MCMV infection. We conclude that MCMV-induced IL-17 downregulation occurs via the stimulation of IL-10 and the suppressor of cytokine signaling (SOCS)-3. Taken together, our results add new information to the immunobiology of HCMV and to our basic understanding of the pathogenesis of AIDS-related HCMV retinitis.

Thesis (Ph.D.)--University of Alberta, 2010. / A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of Doctor of Philosophy, Department of Biochemistry. Title from pdf file main screen (viewed on February 12, 2010). Includes bibliographical references.

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The established model used for evaluating potential therapies for retinal disease has significant limitations. A new model is proposed to account for these limitations: the visual adaptation model. The visual adaptation model was developed to provide a novel approach for testing potential treatments for retinal disease, and the work in this thesis provides empirical support for this model. Specifically, we evaluated two potential therapies for retinal degenerative disease and examined their effects on vision and retinal anatomy. In addition, the profile of retinal reorganization and its functional correlates were examined in RCS rats and transgenic rats which express a rhodopsin mutation; however, immunohistological work targeted one specific line (S334ter-4). Collectively, these studies provide evidence that supports the retinal adaptation model. These studies also provide a novel view of retinal and visual function in retinal disease which should be considered when evaluating treatments involving retinal degeneration. / xvii, 205 leaves : ill. ; 29 cm. --

Thesis (Ph. D.)--University of Washington, 1999. / Vita. Includes bibliographical references (leaves [78]-86).

Rhodopsin-linked retinitis pigmentosa (RP) is the most common form of autosomal dominant RP, an inherited retinal degeneration, in which rod degeneration is followed by secondary cone loss leading to loss of vision and blindness. The overall objective of this work was to develop an optimized gene replacement therapy, delivering the rhodopsin gene for rhodopsin- linked RP and establish whether secondary cone loss can be delayed. A fast-acting single mutant serotype 8 self-complementary adeno-associated virus vector was produced containing the human rhodopsin promoter and the human rhodopsin coding sequence. In vivo studies in rhodopsin knockout mouse showed that the vector administration led to widespread and robust expression of the transgene. Subretinal injection of the vector into three-week pups of rhodopsin knockout mice with cones expressing green fluorescent protein showed restoration of rod-derived electroretinogram (ERG) responses, and preservation of cone- driven ERG responses three months after injection. Similarly, the longitudinal follow-up with confocal scanning ophthalmoscopy found preservation of fluorescent cones up to three months after injection. Overall, these data provided evidence that the designed vector resulted in significant benefit to rod photoreceptors as well as in delay in secondary cone degeneration and built a basis for future use of this vector on dominant models of RP.

La rétinite pigmentaire est une maladie héréditaire rétinienne menant à la cécité, et pour laquelle il n’existe aucun traitement. La cause la plus fréquente des formes autosomiques dominantes de la maladie est une mutation ponctuelle dans le gène de la rhodopsine (RHO) induisant la mort des photorécepteurs (PR). Pour éviter la dégénérescence des PR, la stratégie thérapeutique doit supprimer l’expression de la protéine mutante tout en restaurant celle de la protéine normale et ce à un niveau physiologique. Mon projet était de réparer le pré-ARNm RHO par la technologie SMaRT (trans-épissage (TE) médié par le splicéosome). Ceci nécessite d’introduire par transfert de gène, dans la cellule cible, un ARN exogène, appelé PTM pour molécule pre-ARNm de TE, pouvant induire un épissage en trans.Nous avons créé 20 PTM différents et obtenu un taux maximal de TE in vitro de 40% après co-transfection transitoire des constructions RHO et PTM dans les cellules HEK293T. Nous avons générés des lignées cellulaires d’expression stable de RHO normale ou mutée par transduction lentivirale. Alors que la RHO normale se localise à la membrane plasmique, la mutation induit la rétention cytoplasmique de la protéine. La transfection du PTM dans la lignée cellulaire de RHO mutée a induit du TE, capable de restaurer partiellement la localisation de la RHO réparée à la membrane.Nous avons alors testé le TE in vivo dans un modèle murin humanisé de rétinite pigmentaire. L’injection sous-rétinienne d’un AAV2/8-bRho-PTM a permis le TE in vivo, mais n’a pas suffi à prévenir la dégénérescence des PR observée par SD-OCT (technologie que nous avons améliorée au cours de ce projet). / Retinitis pigmentosa is an hereditary retinal dystrophy involving degeneration of photoreceptors leading to blindness and for which there is currently no treatment. The most frequent cause of autosomal dominant forms of the disease is a point mutation in the rhodopsin gene (RHO). Therapeutic strategy should both suppress mutant protein expression and restore that of the normal one to physiologic level to prevent photoreceptor degeneration. My PhD project was to repair RHO pre-mRNA by SMaRT (Spliceosome Mediated RNA Trans-splicing) technology. This implies to introduce by gene transfer into the target cell an exogenous RNA, called PTM for Pre-mRNA Trans-splicing Molecule. This one was able to promote a splice reaction in trans, leading to the replacement of the mutated exons. We designed 20 different PTM and obtained in vitro a maximum trans-splicing rate of 40% after transient co-transfection of PTM and RHO constructs in HEK293T cells. We then created WT or mutated RHO stable expression cell lines by lentiviral transduction. Mutation induced retention of the protein into the cytoplasm, while the WT RHO was localized to the plasma membrane. We observed that the PTM transfection in the mutated RHO cell line induced trans-splicing, which was able to partially restore localization to the plasma membrane of repaired RHO. We then tested trans-splicing in vivo in mRho+/- RHO P347S+ mice, a humanized heterozygous mouse model of retinitis pigmentosa. After subretinal injection of AAV2/8-bRho-PTM we observed that trans-splicing occurred in vivo. Unfortunately we did not observe by SD-OCT (a technology that we improve in this project) any rescue of the degenerative phenotype.

Retinose Pigmentar (RP) é uma doença hereditária que conduz progressivamente à cegueira. Mais de 150 mutações da rodopsina associadas à RP foram descritas, e causam a alteração da sua conformação. Esta tese testou a hipótese de que pequenas moléculas auxiliam na formação da rodopsina e/ou reduzem a morte dos fotorreceptores. As mutações da RP, N15S e P23H, revelaram diferenças quanto às características e gravidade devido à má-formação das proteínas mutantes. Ligação de pequenas moléculas (retinóides, íons metálicos, clorofilas e antocianinas) à rodopsina foi demonstrada in vitro. O derivado da clorofila, Ce6, mostrou-se mais efetivo, conferindo maior estabilidade e foi então testado em ratos submetidos à degeneração por luz ou em modelos de RP (P23H e S334ter). Observou-se uma proteção contra a degeneração por luz e uma significante diminuição da degeneração no P23H. Em contraste, Ce6 causou um aumento na degeneração dos fotorreceptores do S334ter. Finalmente, resultados clínicos, bioquímicos e in vivo foram comparados e mostraram estar altamente relacionados. / Retinitis Pigmentosa (RP) is an inherited disease that progressively leads to blindness. More than 150 mutations associated with RP are known in rhodopsin, causing its misfolding. This thesis tested the hypothesis that small molecules can rescue folded rhodopsin and/or reduce photoreceptor cell death. RP mutations, N15S and P23H, revealed differences in characteristics and severity of misfolding of the mutant proteins. Binding of small molecule classes (retinals, metal ions, chlorophylls and anthocyanins) to rhodopsin was demonstrated in vitro. The chlorophyll derivative, Ce6, was most effective in conferring stability and therefore tested in rats subjected to light-damage and RP rat models, P23H and S334ter. Protection against the light-induced retinal degeneration and more importantly a significant slowing of the photoreceptor degeneration rate in the P23H rat were observed. In contrast, Ce6 increased photoreceptor degeneration in the S334ter rat. Finally, clinical, biochemical and in vivo rat data were compared and it was found to be highly correlated.